Excessive crying is one of the most frequent causes of visiting pediatricians in infant's first twelve months of life. Its incidence ratio can reach values up to 40%. Infants whom crying persist beyond three months are at risk of adverse outcomes in the school years including anxiety, aggression, hyperactivity, allergy, sleep disorders and even more risk of poor mental health in later years. Excessive crying is not only a serious problem for infants but also for parents and, in general, for family quality of life. Excessive crying leads to parental exhaustion and has many deleterious consequences including difficulties with concentration, loss of patience, frustration, feeling of incompetence, fear of harming the child, early cessation of breastfeeding and reduction of face-to-face interaction with their child. Furthermore, in some cases frustration may result in some kinds of deleterious actions to stop crying such as slapping or shaking the child.
Despite infant crying is commonly associated with evident illness conditions, excessive paroxysmal crying may manifest for no clear reason in apparently healthy and well-fed infants as a result of different conditions of unknown etiology (e.g. infant colic). There is little agreement regarding the origin of such conditions and how they should be defined. However, it has been proposed that they may be well caused by gastrointestinal disturbances, such as immaturity of the gut, spastic colon, food hypersensitivity, altered gut microbiota and gas production.
Traditionally, different drug therapies have being used for reduction of crying and fussing, especially in ‘colicky infants’. One of the most common used drugs is simethicone, but results of clinical trials are not conclusive. Other treatments, based on dicyclomine hydrochloride or cimetropium bromide, have been shown to me more effective, but may lead to undesirable side effects, which limit their use, especially in infants less than 6 months of age.
Herbal remedies have been proposed as an alternative, although scientific evidence is scarce. The commercially available composition ColiMil® (with plant extracts from Matricaria recutita, Foeniculum vulgare and Melissa officinalis) was shown to reduce crying time in a double-blind placebo-controlled clinical trial. In contrast, Mentha piperita extracts has been reported to be ineffective for treatment of infant colic. Moreover, several adverse effects including vomiting, sleepiness, constipation and loss of appetite have been identified in several studies evaluating herbal supplements.
Infant formulas designed to overcome food allergies (i.e. formulas with low lactose content or partially hydrolyzed whey proteins) have been reported to reduce crying episodes. However, these formulas may benefit those infants whose excessive crying is associated mainly to food allergies. High fiber or fiber-enriched formulas have also been proposed as a possible treatment, but no significant differences in symptoms have been found when comparing with a standard formula.
Based on the hypothesis that aberrant intestinal microflora may contribute to excessive crying conditions, great interest on probiotics as a promising treatment has arisen. Probiotics are defined as “living microorganisms, which upon ingestion in certain amounts, exert health benefits beyond inherent basic nutrition”. Several lactic acid bacteria and species from the genus Bifidobacterium or Lactobacillus are probiotic, which implies that they have been shown to promote specific health benefits. Probiotic bacteria must fulfill several requirements related to lack of toxicity, viability, adhesion and beneficial effects. These probiotic features are strain-dependent, even among bacteria of the same species. Therefore, it is important to find those strains exerting the desired probiotic functions.
Only few probiotic compositions for treatment of excessive crying have been studied. The efficacy of a probiotic formula comprising Lactobacillus rhamnosus GG, Lactobacillus rhamnosus LC705, Bifidobacterium breve Bbi99 and Propionibacterium freudenreichii ssp. shermanii JS has been studied without satisfactory results on crying patterns (Mentula, S. et al. “Microbial composition and fecal fermentation end products from colicky infants—A probiotic supplementation pilot”, Microbial Ecology in Health and Disease 2008, vol. 20, no. 1, pp. 37-47). Another study evaluated the effect on colic of an alpha-lactalbumin-enriched and probiotic-supplemented formula (Lactobacillus rhamnosus, Bifidobacterium infantis). The formula reduced feeding-related gastrointestinal side effects, irritability and agitation, but no differences were found in crying duration (Dupont, C. et al. “A-Lactalbumin-Enriched and Probiotic-Supplemented Infant Formula in Infants with Colic: Growth and Gastrointestinal Tolerance” European Journal of Clinical Nutrition 2010, vol. 64, no. 7, pp. 765-767). The beneficial effects of Lactobacillus reuteri DSM 17938 for treatment of colic-related excessive crying have been disclosed in WO2007142596. The efficacy of this strain was assayed with favorable outcomes on infant crying (Savino, F. et al. “Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus Simethicone in the Treatment of Infantile Colic: A Prospective Randomized Study” Pediatrics2007, vol. 119, no. 1: e124-e130; Savino, F. et al. “Lactobacillus reuteri DSM 17938 in Infantile Colic: A Randomized, Double-Blind, Placebo-Controlled Trial” Pediatrics 2010, vol. 126, no. 3: e526-e533; Szajewska, H. et al. “Lactobacillus reuteri DSM 17938 for the Management of Infantile Colic in Breastfed Infants: A Randomized, Double-Blind, Placebo-Controlled Trial”, Journal of Pediatrics 2012, vol. 162, no. 2, pp. 257-262), but was unable to improve intestinal biodiversity (Roos, S. et al. “454 Pyrosequencing Analysis on Faecal Samples from a Randomized DBPC Trial of Colicky Infants Treated with Lactobacillus reuteri DSM 17938”, PLoS ONE 2013, vol. 8, no. 2, e56710 1-5).
In a recent article about the study of intestinal microbiota of infants with colic, it has been proposed that excessive crying may be caused by increased inflammation due to a higher level of pathogens and to a reduction in anti-inflammatory lactobacilli (De Weerth, C. et al. “Intestinal Microbiota of Infants With Colic: Development and Specific Signatures” Pediatrics 2013, vol. 131, Number 2, e550-e558).
WO2007142596 discloses that the strain of Lactobacillus reuteri DSM17938 is useful in the treatment of infant colic due to its ability to promote high amounts of the anti-inflammatory cytokine IL-10.
Pediococcus pentosaceus and Pediococcus acidilactici are commonly used in the fermentation of vegetables and meats and added in fodders as food preservatives to inhibit the growth of food-spoiling bacteria and foodborne pathogens. However, it is believed that there are not products in the market based on Pediococcus pentosaceus for use as probiotic in humans.
A plant derived Pediococcus pentosaceus strain has been disclosed as inducer of secretion levels of interferon-gamma and interleukin IL-12 p70, and suppressor IL-4 productions in ovalbumin sensitized mouse spleen cells. Therefore, the bacteria could effectively stimulate immune activities and showed allergic inhibitory effects due to the induction of such pro-inflammatory cytokines (Jonganurakkun, B. et al. “Pediococcus pentosaceus NB-17 for probiotic use”, Journal of Bioscience and Bioengineering 2008 vol. 106, Issue 1, p. 69-73).
In the same direction, Igarashi T. 2010 discloses that the strain Pediococcus pentosaceus (KKM122) strongly induces the production of the pro-inflammatory cytokine IL-12 (Igarashi T. “Study of the relationship between changes in lactic acid bacterial cell components and stimulation of IL-12 production under salt-stressed conditions”, Bioscience, Biotechnology and Biochemistry 2010, 74, pp. 2171-2175).
Vitali et al. 2012 discloses a study of forty-eight strains of lactic acid bacteria belonging to different species, for their capacity to modulate the synthesis of 27 immune-mediators (cytokines, chemokines and growth factors). Among such immune-mediators, the assay was prepared to detect IL-10. The assay was performed with Caco-2 and PBMC cells stimulated with LPS. The results indicated that few chemokines were stimulated. Immune-mediators with pro-inflammatory activity (IL-17, eotaxin and interferon-gamma) were significantly stimulated by all strains, followed by the cytokine IL-1 beta, the chemokine interferon-gamma-induced protein-10 (IP-10), the cytokine IL-6, and the chemokine macrophage inflammatory protein-1 alpha (MIP-1 alpha). Only few strains increased the synthesis of cytokines with anti-inflammatory activity. Among the strains tested, a strain of Pediococcus pentosaceus isolated from tomato stimulated cytokines IL-1 beta, IL-4, IL-17, and interferon-gamma, but not IL-10. Based on the immune-modulation activity this strain was not selected in the study for further characterization as novel probiotic candidate (Vitali, B. et al. “Novel probiotic candidates for humans isolated from raw fruits and vegetables”, Food Microbiology 2012, 31(1), pp. 116-125).
Therefore, it is clear that excessive paroxysmal crying can have immediate and very serious consequences for both parents and infants. Thus, safe and effective compositions and treatments are required. In this field, probiotics can be considered as a promising alternative to current therapies, but further research is needed.